This is an interesting hypothesis. However, I think the long onset of many phenethylamines is mostly a consequence of kinetics---the time it takes to be absorbed in the bowel, cross the blood-brain-barrier, and possibly the time it takes to enter certain key structures within the brain. This can be experienced subjectively as a progression of different phases during the come-up. Like with mescaline, I would say roughly that the first hour consists of building G.I. effects, the second hour of building body effects, the third hour of building introspective effects, and the experience finally develops fully in the fourth hour. Tryptamines go through a similar progress of phases, but it is much more rapid, and there is a lot more overlap between the peak effects in the body and the mind. MDMA in contrast to something like mescaline is very active in the brain within the first hour, even if it's not trippy.
So, I looked into this and ended up going down a rabbit hole of learning many new things about MDMA that I was not aware of before. It's kind of a fascinating and terrifying substance.
The main new thing I learned is that the majority of the effects of racemic MDMA are produced by (S)-MDMA because it's around three times as potent as (R)-MDMA and produces relatively similar subjective effects in test subjects, but specifically (R)-MDMA also potently inhibits CYP2D6 which is also one of the main enzymes responsible for metabolizing MDMA, which causes (R)-MDMA to both have a dramatically longer elimination half-life than (S)-MDMA on its (like three times longer) and also to extend the elimination half-life of (S)-MDMA and cause its dose-response curve to become less linear and more like exponential when they're both taken in combination, which they usually are since racemic MDMA is the generally preferred form for recreation.
The result of this, according to one set of graphs I saw at least, is that when the average person takes 50 mg of MDMA it's more than halfway eliminated by ten hours and about gone by twenty-four, but when they take 150 mg of MDMA it spikes to almost five times as high of a concentration as 50 mg and at twenty-four hours there's still more MDMA in their plasma than there literally ever was at any point after taking 50 mg; at ten hours there's still more than there literally ever was at any point after taking 100 mg. That's fucking nuts!
Another, relevant, and also fascinating result of this is that the higher dosage of MDMA you take, the faster it reaches peak plasma levels, but if you look at the graphs again you can see that there is a different story going on underneath it. I was planning to bring this up at first because when I first started looking into it, it seemed like the references I was finding were saying that MDMA actually has somewhat similar kinetics to mescaline and DOM, for instance reaching peak plasma levels (the main metric I was really finding) around 2-3 hours after dosing. In fact, in the graphs I saw you can see this quite clearly with the 50 mg concentration timeline, it reaches the peak around three hours after dosing and then immediately starts decreasing. However, in my researching the explanation for the discrepancy with what you said I found a claim that the inhibition of CYP2D6 by MDMA is so intense than when you take a high enough dosage, it causes the levels of itself to build up far more rapidly than it would otherwise, and indeed you can see this in the same graphs I referenced before. With 100 mg, the increase to the peak is much more sharp and seems like it gets there around two hours in, then drops slowly to around three hours, and then starts dropping a bit faster. With 150 mg, there's a massive spike up to the peak that looks like it only takes around like an hour, then an actual rapid significant drop off, then it goes BACK UP to another slightly lesser peak around three hours in, then it starts dropping off slower than the first time but still rapidly after that, then has
another very slight hump up again at ten hours, after which it begins a slower decline that again was still happening at twenty-four hours, with the MDMA levels still being higher than the very peak of 50 mg. What a weird drug!
So frankly, I'm not sure what to think or say now lol. It kind of seems to me like the answer might actually be... both. It seems to me like maybe MDMA itself technically would have kinetics similar to other phenethylamine psychedelics, except that it also has a nonlinear dose-response curve by blocking its own metabolism which also makes its levels spike and fall off much faster than other phenethylamines in sort of a separate, overlapping, blending curve as the dosage increases. Interesting stuff for sure.
I'm not totally swayed in one direction or another yet with what I think it may mean with regard to its subjective effects. I think I need some more time to digest this information.
Regarding your observations, I think a few things need to be taken into consideration. First, MDMA definitely sticks around a lot longer than the 3-4 hours or so during which most people experience the most desirable effects. Second, MDMA and has pretty weak 5-HT2A affinity, so for any trippy effects occur, one needs rather large doses in the first place. Some of these trippy effects probably do come from metabolism to MDA, but MDA is still pretty weak at 5-HT2A compared to its other effects. Third, the large amount of serotonin that is released during the early part of the experience likely competes with the trippy effects of MDXX, both by tying up 5-HT2A and also by strongly activating 5-HT1A which can counter or negate many of the effects of the 5-HT2A agonism. What might be happening at around 4-5 hours into your experience is that the serotonin release drops off by a lot but the drug (and its metabolic product MDA) are still present and no longer have to compete with all that serotonin, which may cause the trippy effects to emerge later.
I still think the relevance of MDMA metabolizing into MDA is debatale, although I could see it being slightly more feasible after reading the kind of stuff I did when researching MDMA metabolism. The thing is just the studies I've seen say that like less than 10% of the MDMA ingested and sometimes as little as like 1.5% seems to metabolize into MDA. It just doesn't seem like a likely significant contributor to me if those numbers are accurate. But I will say, since MDMA blocks its own metabolism via CYP2D6 and that enzyme is specifically not one of the major ones involved in metabolizing to MDMA to MDA, it does seem possible that as the MDMA dosage increases, the ratio of metabolism to MDA also increases, and maybe they're not capturing the full level of metabolism that would be occuring in a rave setting with people taking high and repeated dosages of MDMA compared to just giving a one time 100 mg dosage in a lab setting or something.
I understand what you're saying about the serotonin release but I don't know that I really buy that theory myself.
I don't want to take up too much of your time here with too much of a tangent, but I currently have a separate (but related) theory that a significant portion of the hallucinogenic effects of MDMA are not serotonergic at all but are actually mediated by alpha-2 adrenergic receptor agonism (not sure which subtype) - at least in some people, such as myself. MDMA is a pharmacological clusterfuck so I'm not trying to claim that that's all that it's doing or that how it works has exactly the same explanation for everyone but the theory is that it could at least meaningfully contribute at least sometimes.
The quick rundown is the alpha-2 adrenergic receptor agonism is actually a proven hallucinogenic, euphoric, and analgesic mechanism of action that the recreational drug scene has mostly missed for some reason, the but the medical community is very aware of it. If you read case reports about pharmaceutical drugs that have this mechanism of action selectively, it's common to see reports of these "side effects" with the doctors who write them also saying things like, "Of course, alpha-2 agonists are commonly known to cause hallucinations." and stuff like that. They tend to be prescribed for ADHD and high blood pressure, and obviously the goal would be to prescribe them at non-hallucinogenic dosages, but the fact that they're listed as a common side effect does suggest that maybe they'd be typical at higher dosages. I'm guessing that maybe the reason the recreational drug community hasn't picked up on them is just because the pharmaceutical drugs that work in this way are, for whatever reason, just not very fun compared to other recreational options. However, an actually quite large number of already popular recreational drugs already are known to bind to alpha-2 adrenergic receptors as well and most likely behave as agonists based on what's known about their pharmacological activities in general. Most psychedelics do have some affinity to these receptors, for example, although whether they bind there in a range that's close enough to their affinity for 5-HT2A receptors to be relevant varies significantly from one psychedelic to the next.
Almost all psychedelics that I've seen data for are still more selective for 5-HT2A receptors than for alpha-2 adrenergic receptors. In the realm of indoles, it seems having a simple tail makes them have probably the lowest amount of alpha-2 adrenergic receptor affinity, whereas having a very bulky tail makes the probably have the highest amount. LSD has one of the highest alpha-2 adrenergic receptor affinities I've seen a psychedelic have without exceeding its 5-HT2A receptor affinity, while some studies show DPT as being more selective for alpha-2 than for 5-HT2A. In the realm of phenethylamines, 2C-x and DOx molecules do often have alpha-2 affinity that seems to be at least somewhat less than their 5-HT2A affinity and sometimes a lot less. Mescaline, however, is actually notably more selective for alpha-2 than for 5-HT2A, and is by far the most alpha-2-selective psychedelic I've seen characterized so far, unless you also include the empathogen psychedelics like MDMA and MDA, which are even more alpha-2-selective than mescaline (compared to 5-HT2A rececptor agonism, I mean, but not necessarily in comparison to monoamine release).
Recently, I began experimenting with CBG (cannabigerol) in an attempt to elucidate some of this. CBG does have some activities similar to other phytocannabinoids, like having various agonist or antagonist effects at cannabinoid receptors, 5-HT1A receptors, TRP channels, PPARs, etc., but, unlike the others that have been characterized so far, it is also a highly potent alpha-2 adrenergic receptor agonist, more potent there than at any of these other sites too. I have been experimenting with many phyotcannabinoids used primarily orally as of late and tend to be highly sensitive to getting psychoactive effects from them if they can produce them, so I figured I'd probably be able to suss out the similarities and differences compared to CBG, and probably get good effects out of CBG in general, and thought that perhaps CBG might make a good reference for what an alpha-2 adrenergic receptor agonist should be like on its own, removed from 5-HT2A receptor agonism or monoamine releasing agent effects or most other things that are simultaneously done by other alpha-2 adrenergic receptor agonists I've had access to before.
I quickly found that, similarly to what others have said, CBG for me has some effects that feel somewhat stimulating at lower dosages but also become a little heavier and more sedative-like at higher dosages. It is not a very intoxicating substance, quite lucid in fact, although I would say it's more intoxicating than I expected from what I read online, and even at low dosages reminds me a bit of the euphoric stimulant feelings of MDMA, although kind of more on a like caffeine-like level, certainly not the overt and heavy hit of MDMA, but definitely subjectively similar-feeling nonetheless. Walking around outside in a breeze feels extremely pleasant in a way that gives me good flashbacks to past memorable MDMA experiences, for instance. Additionally, I do in fact hallucinate from CBG, although in a more subtle way compared to its other effects unless a high dosage is taken or its combined with THC (THC and CBG is actually a pretty crazy combo for me). While it was not common for me to find accounts of people hallucinating from CBG when reading about it online, I did find the occasional mention of someone getting visuals from it or describing it as "quasi-psychedelic" or something along those lines, and I strongly suspect that what they were referring to is that same sort of effects I'm getting and describing here. Perhaps CBG is likely to be weak enough in this way that you have to have some sensitivity to it or to hallucinating in general to get these sort of effects from it more readily, is what I'd guess anyway; like I said, I tend to get good effects from phytocannabinoids in general and also tend to hallucinate quite easily from many things (and also have mental health conditions that may even make this more likely) so I may just happen to fit nicely into this category.
The hallucinations I have experienced from CBG so far come mostly in the form of visions. At 15 mg, these visions were extremely simple and fleeting, involving things like seeing jewelry flash by for a second. There's also some increase in visual noise, the static behind my closed eyes looks sort of golden yellow and like it's ready to be a stage for visions to occur but they're not really at the point of occuring yet. At 30 mg, I began seeing images and scenery that would actually remain for more than a flash, but also would linger for too long, being interestingly detailed but not changing very much or having a lot of movement within themselves. I see things like lots of three-dimensional but somewhat cartoony or virtual faces, all mashed together like wailing walls of piles of skulls, with ornate Brazilian carnival mask-like designs painted on them, and mysterious cloaked figures roaming through dark fields in strange netherworld scenes. 30 mg was also the best dosage for stimulation for me, getting me to unpack boxes at my apartment that I had been neglecting otherwise, and having it still be very easy to ignore those visions if I didn't consciously choose to focus on them. At 45 mg, the stimulation became too heavy and I spent the day lazing around in the euphoria instead, and found it very difficult to focus on anything other than the visions I was getting, not that I would have wanted to anyway. At that 45 mg, the visionary experience finally reached the point of feeling more like a complete trip, being like a constant animated slideshow of interesting, mundane but also silly and goofy, highly synesthetic imagery just flowing by my mind's eye. A lot of the visions I saw were related to animals - things like seeing from the perspective of an eagle soaring above a valley, or from a rabbit drinking from a bowl of water in my parents' backyard being watched through the sliding glass door by myself - while others had decidedly modern themes. One of my favorites was one where I threw my head back in real life in euphoria, and the feeling of throwing my head back transformed into watching a game show where a constestant played that carnival game where you hit a button with a mallet to try to get the thing to slide up and hit the bell, with the thing sliding up being my throwing my head back and it hitting the bell and causing me to hear and feel the ring and vibration at the moment my head was thrown all the way back, lol. For this trip, there was also what I would describe as sort of a tribal-feeling spiritual energy to everything not unlike I've experienced on powerful MDMA trips, that seemed to go along with the "this is finally a deeper level of tripping compared to lower dosages" vibe of it. Also, while most of the trip was still just visions like this, at one point late at night I was using my phone while sitting in bed with the lights off and the distortion from the light caused my bedsheets to extremely vidily and clearly start transforming into faces similar to the ones I had seen in my visions from 30 mg.
I won't go as deep into these but I've also experimented with 1:1 THC and CBG gummies at 10 mg and 20 mg of each. The 20 mg definitely produce a decent trip for me, blending both the lower dosage CBG style and my typical oral THC trip style into something that I would say seems like more than the sum of its parts. THC mixes really well with CBG for me in general, dramatically intensifying the visionary effects although also making them more 2D and cartoony with paler colors, but also more animated than they would normally otherwise be at the same dosage. And the euphoric and analgesic effects and such of the highs mix really well too. Also, one time I took 20 mg while having a manic episode and had one of the most ridiculously extreme altered states of my life where I thought I was seeing the karmic geometry to my entire life laid out clearly and could see people around me moving in ways like hyperspatial entities revealing the fractal nature of the multiverse around me and became connected to the hive mind of the collective consciousness of every being in reality to be the volunteer in a demonstration of how magic works, but that one is kind of a special circumstance, heh....
Anyway, something that's very relevant for me to mention about my 45 mg CBG experience, when I finally had what felt like a "full trip" on it, is that I actually had vivid visions on it that were exact visions that I've only ever seen before one time a long time ago when I took more 700 mg of MDMA and hallucinated extremely hard for many hours, and not once on anything ever since, in addition to, again, having other general feelings that reminded me of tripping hard on MDMA, like the tribal spiritual energy thing, and just generally having a very powerful and satisfying euphoria of a similar nature too, although without any effects that felt like monoamine releasing agents. In fact, the only thing CBG feels more similar to me so far than MDMA is nutmeg essential oil, which I also find to feel extremely similar to tripping on MDMA except without a monoamine releasing agent component, and correspondingly also specifically feel that MDMA basically feels like taking something like nutmeg essential oil or CBG but also taking something reminiscent of amphetamine at the same time. Nutmeg essential oil even reminds me of MDMA in a way where it feels like a euphoric part comes on fast but it still slowly gets trippier over a few more hours and then after a few more hours the high and trip mostly drop off but it still kind of hangs around for more than day, just, again, without the monoamine releasing agent component to it.
There's unfortunately very little pharmacological data about the chemicals in nutmeg essential oil that is relevant to their recreational use. However, the most prominent three chemicals and the ones by far the most likely responsible for the bulk of the subjective effects are the allylbenzenes, myristicin, elimicin, and safrole. Safrole is literally just MDMA and MDA except with the meth/amphetamine tail replaced with an allyl group instead, it's an almost identical molecule. However, that slight change is why safrole is not a monoamine releasing agent, and although we don't have binding data, seems likely to dramatically or entirely reduce 5-HT2A receptor binding potential as well, from what I understand. I've argued with people here before about how psychedelic nutmeg essential oil seems despite this, and now I'm shifting to thinking that this could be because unlike 5-HT2A receptor agonism, perhaps these allylbenzenes could still retain alpha-2 adrenergic receptor agonism and produce effects similar to CBG and MDMA in this way. Elemicin is the allyl analogue of mescaline in the same way that safrole is of MDMA and MDA, and myristicin is that of MMDA, which is described as being similar to MDMA and MDA except having even more of that relatively unique hallucinogenic style than either of them, and specifically those hallucinogens are usually described as mundane but meaningful visions or with terms like "brain movies" as I've seen multiple times, which to me sounds literally exactly like the kinds of effects I got from the high dosage of CBG. And I haven't taken mescaline personally so I can't speak to that, and I know how much people get visuals and stuff from it seems to vary a lot from one person to the next, but I've most definitely heard people describe visions of this nature from mescaline while specifically calling them out as distinct from other psychedelics before too....
The thing about CBG is that it literally looks like a complex derivative of mescaline and has a much more fucked up tail structure compared to mescaline than myristicin, elemicin, and safrole do, and yet it still has potent alpha-2 adrenergic receptor agonism just like mescaline does, so I'm more willing to believe that the allylbenzenes could retain that sort of activity as well, compared to the supposedly much less likely 5-HT2A receptor agonism.
So, that's all to say, I'm kind of on the alpha-2 adrenergic receptor agonism train right now. It seems like it could make sense to me, anyway, and seems to be helping successfully guide me through finding other similar experiences with other drugs right now as well, so I'm enjoying it at least.
CBG rocks by the way (regardless of the responsible mechanism), I've been meaning to come on here and rave about all of this anyway, I've just been trying to sort through it all first and also work on lots of other stuff in the meantime.
Oh, I forgot to get back to this but I do actually feel like both CBG and nutmeg essential oil remind me somewhat of bulky indoles specifically in the way that differentiate them from less bulky indoles sometimes too, like going along with LSD and DPT having much higher alpha-2 adrenergic receptor affinity than things like psilocin and DMT, for instance. Like I also once smoked 4-AcO-DET and saw netherworld scenes with dark temples with piles of skulls outside them, very much like the visions I got on 30 mg of CBG. And DPT gave me some open eye visual faces similar to the ones I saw on my bed at night on 45 mg of CBG too. Also, my recent LSD trips involved a lot of visions of fancy/classy fashion like jewerly and luxurious clothing similar to some of my recurring CBG visions. So I've thought quite a lot into other comparisons too, regardless of whether the theory is actually accurate or not.
I don't know how to fit this all into the model of wacky MDMA kinetics as mentioned above and stuff yet either. I'm just sharing that this is the theory of what the subjective effects seem the most like to me that I've had in my head lately.
I never get the "crash" that so many people get after 3-4 hours or whatever. I definitely feel the effects diminish to like 20%, but then they linger at a low level for a long time---into the next day really. My wife agrees and says a single MDMA dose could keep her rolling for something like 24 hours.
Yeah, I definitely feel it for more than day usually, sometimes more than two in at least some minor way. I guess the aforementioned crazy kinetics help to explain that. These pills definitely feel like they were dosed extra high to me too because even given this the "main" roll felt like it lasted like 10-12 hours to me, much more than I was used to from back in the day. I looked up some pill ID data (which I really should have done beforehand) and found that pill dosages these days indeed tend to be huge in general compared to the time and place where I first started rolling back in the day. I definitely need to take half next time and I might go even lower than that after that depending on how that goes.
For me the real MDMA crash doesn't hit until around 5-7 days later, and in addition to some harsh mood swings, I also often get sick.
This started for me around the time of my last post and hasn't ended yet (it's been six days now). It's not that bad compared to some things (I tried 7-hydroxymitragynine recently and it actually made me crash very, very hard to the point of feeling genuinely sick, much worse than I've gotten from this) but it is a little annoying because of how long it hangs on. I just feel a little weak, out of it, and like I've got some digestive issues. They're all weak enough that I can ignore them when I've got things to focus on but they keep popping back up to nag at me.
This all being said, like I said I think I took too much this time. Maybe it won't be so bad when I take a more appropriate dosage.
The last time I took MDMA, this crash was quite bad. I think I managed to abort or cancel it by taking some mushrooms, but I decided at that point that the after-effects are not worth the usually lackluster (for me) peak effects. With true psychedelics, I almost always feel better than before I tripped when days 5-7 roll around. The other thing is that I don't notice their entactogenic effects suddenly dropping after 3-4 hours but persisting for the whole duration of the experience (and then some). For me personally, the entactogenic psychedelics like most 2C-X are just superior all the way around.
For me other psychedelics just don't do what MDMA does. It has very unique and specific therapeutic effects for me that I don't think I really get from other drugs in general. I actually consider this experience I had to be one of the most important drug experiences I've had in a very long time and possibly ever (I didn't really go into why in my post explaining the experience, it's very personal and context-specific). I'd be happy I took it even if it made me feel even worse afterward than it has. I might be less inclined to want to take it again than I am if that was the case, though....
If it doesn't do something particularly unique for you then I get it. It's kind of a janky ass drug. I actually do like it a lot though. Back in the day it was one of my favorite drugs and the only reason I stopped using it for so long is because I abused it so heavily that it lost all value and every experience I tried to have after that became entirely negative. I am hoping that now that I have a fresh chance at forming a relationship with it after so long, I can be at least a little bit more responsible with it this time around and have it remain a positive force in my life.
(I made a poor start by just taking one of those whole pills somewhat recklessly instead of cutting it in half but I'm working on it lol.)
MDMA and most common "true" psychedelics share a significant affinity at 5-HT2B, and evidence suggests that activation of 5-HT2B enhances serotonin release considerably. MDMA's serotonin releasing effects may even depend on activation of 5-HT2B, despite its strong affinity at the serotonin transporter. It's possible that the 5-HT2B action is key to the entactogenesis, and that its specific action at the serotonin transporter mostly serves to cause the abrupt drop in serotonin transmission following the early effects and the associated crashes and neurotoxicity.
That said, it does appear that 5-HT2B active psychedeilcs taken after the peak can extend pleasant effects associated with serotonin release by MDMA. Therapists in Shulgin's circle who would often follow MDMA with 2C-B or MEM, which were said to be capable of maintaining and enhancing the window for much longer than would be the case with MDMA alone. MEM is interesting. I think it has relatively high affinity for 5-HT2B versus 5-HT2A, meaning it's not very trippy, but it probably lacks the serotonin (and DA/NE) transporter activity of MDMA. Did you ever get to try MEM? I've always wanted to try it myself.
I've not taken MEM, no. I'd love to try it, as I love TMA-2, which for the record I also found to be very fun in an MDMA-like way compared to the average phenethylamine psychedelic, although still in ways more comparable to them than to MDMA itself.
